Exercise Evaluation Randomised Trial (EXERT): a randomised trial comparing GP referral for leisure centre-based exercise, community-based walking and advice only.
To evaluate and compare the effectiveness and cost-effectiveness of a leisure centre-based exercise programme, an instructor-led walking programme and advice-only in patients referred for exercise by their GPs. A single-centre, parallel-group, randomised controlled trial, consisting of three arms, with the primary comparison at 6 months. Assessments were carried out at Copthall Leisure Centre in Barnet, an outer London borough, and exercise programmes conducted there and at three other leisure centres and a variety of locations suitable for supervised walking throughout the borough. Participants were aged between 40 and 74 years, not currently physically active and with at least one cardiovascular risk factor. The 943 patients who agreed to participate in the trial were assessed in cohorts and randomised to one of the following three arms: a 10-week programme of supervised exercise classes, two to three times a week in a local leisure centre; a 10-week instructor-led walking programme, two to three times a week; an advice-only control group who received tailored advice and information on physical activity including information on local exercise facilities. After 6 months the control group were rerandomised to one of the other trial arms. Assessments took place before randomisation, at 10 weeks (in a random 50% subsample of participants), 6 months and 1 year in the leisure centre and walking arms. The control participants were similarly assessed up to 6 months and then reassessed at the same intervals as those initially randomised to the leisure centre and walking groups. The primary outcome measures were changes in self-reported exercise behaviour, blood pressure, total cholesterol and lipid subfractions. Secondary outcomes included changes in anthropometry, cardiorespiratory fitness, flexibility, strength and power, self-reported lifestyle behaviour, general and psychological health status, quality of life and health service usage. The costs of providing and making use of the service were quantified for economic evaluation. There was a net increase in the proportion of participants achieving at least 150 minutes per week of at least moderate activity in the sport/leisure and walking categories in all three study groups: at 6 months, the net increases were 13.8% in the leisure centre group, 11.1% in the walking group and 7.5% in the advice-only group. There were significant reductions in systolic and diastolic blood pressure in all groups at each assessment point compared with baseline. There were also significant and sustained improvements in cardiorespiratory fitness and leg extensor power, and small reductions in total and low-density lipoprotein cholesterol in all groups, but there were no consistent differences between the groups for any parameter over time. All three groups showed improvement in anxiety and mental well-being scores 6 months after the beginning of the trial. Leisure centre and walking groups maintained this improvement at 1 year. There were no differences between groups. Costs to the participants amounted to pound 100 for the leisure centre scheme and pound 84 for the walking scheme, while provider costs were pound 186 and pound 92, respectively. Changes in overall Short Form 36 scores were small and advice only appeared the most cost-effective intervention. The results of this trial suggest that referral for tailored advice, supported by written materials, including details of locally available facilities, supplemented by detailed assessments may be effective in increasing physical activity. The inclusion of supervised exercise classes or walks as a formal component of the scheme may not be more effective than the provision of information about their availability. On cost-effectiveness grounds, assessment and advice alone from an exercise specialist may be appropriate to initiate action in the first instance. Subsidised schemes may be best concentrated on patients at higher absolute risk, or with specific conditions for which particular programmes may be beneficial. Walking appears to be as effective as leisure centre classes and is cheaper. Efforts should be directed towards maintenance of increased activity, with proven measures such as telephone support. Further research should include an updated meta-analysis of published exercise interventions using the standardised mean difference approach.


[Importance of a screening system in the prevention of diseases of the lumbosacral division of the peripheral nervous system].
An automated screening system for prophylactic examinations is offered. The system enables one to reveal early compensated forms of lumbar osteochondrosis, as well as persons with an increased risk of that disease. The system is based on a statistical analysis of the lumbar osteochondrosis risk factors revealed in a particular individual, and involves the use of a computer. The practical use of this system at large industrial plants has made it possible to reveal potential patients to whom individual therapeutic and prophylactic complexes were administered. It is shown that the size of the risk groups in workshops depends on the character of the production operations performed and on the working conditions, the correlates with the prevalence of the disease in each particular collective body.


Efficacy of doripenem and ertapenem against KPC-2-producing and non-KPC-producing Klebsiella pneumoniae with similar MICs.
In the clinical setting, the choice of definitive drug therapy is typically guided by the antimicrobial susceptibility profile of the infecting organism. We evaluated the activity of doripenem and ertapenem against Klebsiella pneumoniae isolates with similar MICs that exhibited KPC-based and non-KPC-based genotypes. Five doripenem-non-susceptible K. pneumoniae isolates, three producing KPC carbapenemases and two exhibiting porin modifications plus AmpC β-lactamase production, were tested in a neutropenic murine thigh infection model. The ertapenem MIC for all isolates was >32 mg/L. Regimens of 2 g of doripenem every 8 h (4 h infusion) and 1 g of ertapenem every 24 h (0.5 h infusion) simulating human concentration-time profiles were administered 2 h after inoculation. The change in bacterial density was evaluated after 24 h of therapy. Consistent with the observed MICs, treatment with ertapenem resulted in minimal activity against all isolates tested. When comparing the activity of doripenem between the KPC and non-KPC producers with doripenem MICs of 8 mg/L, significantly better activity was noted for the non-KPC producer (P<0.001). Likewise, when comparing the two KPC-producing isolates with doripenem MICs of 24 mg/L and >32 mg/L with the non-KPC producer with an MIC of 32 mg/L, significantly greater activity was noted for the non-KPC producer (P<0.001). When doripenem MICs were similar, activity was greater for non-KPC-producing isolates when compared with KPC producers. While the in vitro MIC is typically the sole method utilized to aid in drug selection, these data suggest that the genetic driver behind these MICs may also play a role in predicting in vivo activity.


Single-molecule detection with a millimetre-sized transistor.
Label-free single-molecule detection has been achieved so far by funnelling a large number of ligands into a sequence of single-binding events with few recognition elements host on nanometric transducers. Such approaches are inherently unable to sense a cue in a bulk milieu. Conceptualizing cells' ability to sense at the physical limit by means of highly-packed recognition elements, a millimetric sized field-effect-transistor is used to detect a single molecule. To this end, the gate is bio-functionalized with a self-assembled-monolayer of 1012 capturing anti-Immunoglobulin-G and is endowed with a hydrogen-bonding network enabling cooperative interactions. The selective and label-free single molecule IgG detection is strikingly demonstrated in diluted saliva while 15 IgGs are assayed in whole serum. The suggested sensing mechanism, triggered by the affinity binding event, involves a work-function change that is assumed to propagate in the gating-field through the electrostatic hydrogen-bonding network. The proposed immunoassay platform is general and can revolutionize the current approach to protein detection.


Short duty cycle destabilizes a half-center oscillator, but gap junctions can restabilize the anti-phase pattern.
Mutually inhibitory pacemaker neurons with duty cycle close to 50% operate as a half-center oscillator (anti-phase coordination, i.e., 180 degrees out of phase), even in the presence of weak to modest gap junctional coupling. For electrical coupling strength above a critical value synchronization occurs. But, as shown here with modeling studies, the effects of electrical coupling depend critically on a cell's duty cycle. Instead of oscillating either in-phase or anti-phase, model cells with short duty cycle express additional rhythmic patterns, and different transitions between them, depending on electrical coupling strength. For weak or no electrical coupling, cells do not oscillate in anti-phase but instead exhibit almost in-phase activity. Strengthening this weak coupling leads to stable anti-phase activity. With yet stronger electrical coupling stable inphase (synchrony) emerges but it coexists with the anti-phase pattern. Thus the network shows bistability for an intermediate range of coupling strength. For sufficiently strong electrical coupling synchrony is the network's only attracting rhythmic state. Our results, numerical and analytical (phase plane analysis), are based on a minimal but biophysically motivated pacemaker model for the slowly oscillating envelope of bursting neurons. However, illustrations for an Hodgkin-Huxley model suggest that some of our results for short duty cycle may extend to patterning of repetitive spikes. In particular, electrical coupling of intermediate strength may promote anti-phase activity and provide bistability of anti-phase and in-phase spiking.


Characterization of macrozoospermia-associated AURKC mutations in a mammalian meiotic system.
Aneuploidy is the leading genetic abnormality that leads to miscarriage, and it is caused by a failure of accurate chromosome segregation during gametogenesis or early embryonic divisions. Aurora kinase C (AURKC) is essential for formation of euploid sperm in humans because mutations in AURKC are correlated with macrozoospermia and these sperm are tetraploid. These mutations are currently the most frequent mutations that cause macrozoospermia and result from an inability to complete meiosis I (MI). Three of these mutations AURKC c.144delC (AURKC p.L49Wfs22), AURKC c.686G > A (AURKC p.C229Y) and AURKC c.744C > G (AURKC p.Y248*) occur in the coding region of the gene and are the focus of this study. By expressing these alleles in oocytes isolated from Aurkc-/- mice, we show that the mutations have different effects on AURKC function during MI. AURKC p.L49Wfs22 is a loss-of-function mutant that perturbs localization of the chromosomal passenger complex (CPC), AURKC p.C229Y is a hypomorph that cannot fully support cell-cycle progression, and AURKC p.Y248* fails to localize and function with the CPC to support chromosome segregation yet retains catalytic activity in the cytoplasm. Finally, we show that these variants of AURKC cause meiotic failure and polyploidy due to a failure in AURKC-CPC function that results in metaphase chromosome misalignment. This study is the first to assess the function of mutant alleles of AURKC that affect human fertility in a mammalian meiotic system.


Superior vena cava syndrome: treatment with catheter-directed thrombolysis and endovascular stent placement.
To evaluate use of catheter-directed thrombolysis and/or endovascular stent placement to treat superior vena cava (SVC) syndrome. Fifty-nine consecutive patients with SVC syndrome were studied. The cause was underlying malignancy in 43 and benign disease in 16. All patients underwent bilateral upper-extremity venography. The SVC was occluded in 31 cases and stenosed in 28. Twenty-seven patients underwent catheter-directed thrombolysis; 51 underwent endovascular stent placement. Patency was defined in terms of absence of symptoms and signs of SVC syndrome. Technical success was achieved in 56 of 59 patients (95%). Among 42 patients with underlying malignancy (mean follow-up, 7.0 months; range, 1-34 months), primary clinical patency was achieved in 33 (79%) and secondary clinical patency was achieved in 39 (93%). Among 13 patients with benign disease (mean follow-up, 17.0 months; range, 1-27 months), primary clinical patency was achieved in 10 (77%) and secondary clinical patency was achieved in 11 (85%). Four patients were lost to follow-up. Periprocedural mortality and morbidity rates were 3% (two of 59 patients) and 10% (six of 59 patients), respectively. Catheter-directed thrombolysis and endovascular stent placement is a safe and effective treatment for SVC syndrome.


Perylene bisimide hydrogels and lyotropic liquid crystals with temperature-responsive color change.
The self-assembly of perylene bisimide (PBI) dyes bearing oligo ethylene glycol (OEG) units in water affords responsive functional nanostructures characterized by their lower critical solution temperature (LCST). Tuning of the LCST is realized by a supramolecular approach that relies on two structurally closely related PBI-OEG molecules. The two PBIs socially co-assemble in water and the resulting nanostructures exhibit a single LCST in between the transition temperatures of the aggregates formed by single components. This permits to precisely tune the transition from a hydrogel to a lyotropic liquid crystal state at temperatures between 26 and 51 °C by adjusting the molar fraction of the two PBIs. Owing to concomitant changes in PBI-PBI interactions this phase transition affords a pronounced color change with "fluorescence-on" response that can be utilized as a smart temperature sensory system.


PU.1 expression is modulated by the balance of functional sense and antisense RNAs regulated by a shared cis-regulatory element.
The transcription factor PU.1 is an important regulator of hematopoiesis; precise expression levels are critical for normal hematopoietic development and suppression of leukemia. We show here that noncoding antisense RNAs are important modulators of proper dosages of PU.1. Antisense and sense RNAs are regulated by shared evolutionarily conserved cis-regulatory elements, and we can show that antisense RNAs inhibit PU.1 expression by modulating mRNA translation. We propose that such antisense RNAs will likely be important in the regulation of many genes and may be the reason for the large number of overlapping complementary transcripts with so far unknown function.


[Cutaneous cysts, minor surgery].
For the nursing profession, the practice of minor surgery means the recovery of an activity which possesses a long historical tradition in our profession and an experience for nurses to provide a specific service in health care. The incorporation of minor surgery as one of the services offered by Primary Outpatient Clinic Care is taking place slowly but surely, especially in light of the advantages it provides. For several years now, some health professionals, nurses and doctors belonging to the Andalucian Health Services, have been actively working on the development and implementation of Minor Surgery Programs inside the Health Clinics of our community. One of our lines of work has been the development of protocols for the treatment of the most habitual lesions by means of minor surgery. Among these are cutaneous cysts whose protocol we present in this article.


Varied pore organization in mesostructured semiconductors based on the [SnSe4](4-) anion.
Open framework metal chalcogenide solids, with pore sizes in the nano- and mesoscale, are of potentially broad technological and fundamental interest in research areas ranging from optoelectronics to the physics of quantum confinement. Although there have been significant advances in the design and synthesis of mesostructured silicas, the construction of their non-oxidic analogues still remains a challenge. Here we describe a synthetic strategy that allows the preparation of a large class of mesoporous materials based on supramolecular assembly of tetrahedral Zintl anions [SnSe4]4- with transition metals in the presence of cetylpyridinium (CP) surfactant molecules. These mesostructured semiconducting selenide materials are of the general formulae (CP)4-2xMxSnSe4 (where 1.0 < x < 1.3; M=Mn, Fe, Co, Zn, Cd, Hg). The resulting materials are open framework chalcogenides and form mesophases with uniform pore size (with spacings between 35 and 40 A). The pore arrangement depends on the synthetic conditions and metal used, and include disordered wormhole, hexagonal and even cubic phases. All compounds are medium bandgap semiconductors (varying between 1.4 and 2.5 eV). We expect that such semiconducting porous networks could be used for optoelectronic, photosynthetic and photocatalytic applications.


Effect of Vitamin D Supplementation on Weight Loss, Glycemic Indices, and Lipid Profile in Obese and Overweight Women: A Clinical Trial Study.
Vitamin D (vit D) deficiency has defined as a health problem worldwide. World Health Organization (WHO) has declared that obesity is an epidemic of the 21st century. Previous studies have shown that obesity may increase the risk of Vit D deficiency. Furthermore, other studies have demonstrated that vit D insufficiency was accompanied with higher risk of type 2 diabetes, cardiovascular diseases, hypertension, and obesity. The aim of this study was to survey the effect of vit D supplementation on weight loss among overweight and obese women aged 20-40 years in Isfahan. This double-blind clinical trial was done on 50 overweight and obese women who were divided into two groups, in which one group received vit D supplements and the other group received placebo. Intervention group received vit D with dozes 50,000 IU/w for 6 weeks. The levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), fasting blood sugar (FBS), insulin (ins), homeostasis model assessment of ins resistance (IR), C-reactive protein (CRP), height, weight (WT), waist circumference (WC), hip circumference (HC), and blood pressure (BP) were measured before and after intervention. After using vit D supplementation for 6 weeks, WT, WC, and body mass index (BMI) were decreased significantly and serum vit D increased significantly compared to control group (P < 0.001). Other factors including TC, TG, LDL-c, HDL-c, FBS, CRP, ins, IR, and waist to hip ratio (WHR) did not change significantly (P > 0.05). After 6 weeks of intervention, the means of WT, BMI, WC, and HC decreased significantly. Previous studies have shown that vit D deficiency was more prevalence in obese people and there was an inverse association among vit D with BMI and WC. The relationship between vit D and lipid profiles such as glycemic indexes, anthropometric indexes, CRP, and BP is not clear and needs more study in the future.


Prognosis and reproducibility of new and existing binary grading systems for endometrial carcinoma compared to FIGO grading in hysterectomy specimens.
The current International Federation of Gynecology and Obstetrics (FIGO) grade in endometrial carcinomas requires the evaluation of histologic features with proven prognostic value but with questionable reproducibility. This study tests the prognostic power and reproducibility of a new binary grading system. Specimens from 254 hysterectomies were graded according to the new 3- and 2-tiered FIGO grading systems described by Alkushi et al. The selected morphologic parameters for the new grading system included the presence of predominant solid or papillary architecture pattern, severe nuclear atypia, tumor necrosis, and vascular invasion. The Cox proportional hazards and κ statistics were used for comparisons. On multivariate analysis, and looking at all tumor cell types, the 4 tested grading systems were independent predictors of survival, with the 3-tiered FIGO grading system being the most predictive (P = 0.005). In the subset of endometrioid tumors, the 3- and 2-tiered FIGO grading systems and the new grading system retained their statistical significance as predictors of survival (P = 0.004, P = 0.03, and P = 0.007, respectively), whereas the grading system of Alkushi et al did not (P = 0.1). In nonendometrioid tumors, the new grading system proved to be the best predictor of survival, reaching near statistical significance (P = 0.06). The new grading system had acceptable intraobserver and interobserver reproducibility assessment (κ = 0.87 and κ = 0.45, respectively). The 3-tiered FIGO grading system retained its superior prognostic power. However, available binary grading systems remain an attractive option by being highly reproducible and by eliminating the clinical ambiguity of intermediate grades of disease.


A new mutation (db3J) at the diabetes locus in strain 129/J mice. I. Physiological and histological characterization.
A spontaneous recessive mutation appearing in strain 129/J mice at the diabetes (db) locus on Chromosome 4 has been characterized. The new allele, designated db3J, produced hyperphagia and severe obesity. Mutants weighed in excess of 70 g by 6 months of age, compared to 22-28 g for lean littermates. Although the disease was similar to the mild hyperglycaemia-severe obesity syndrome exhibited by db gene presentation on the C57BL/6J inbred background, the syndrome in 129/J mice reduced lifespan, with mutants exhibiting sudden weight loss, hypoglycaemia, and a 67% mortality between 6 and 14 months of age. Mutant males, but not females, were transiently hyperglycaemic between 2 to 4 months of age, attaining a maximum mean blood sugar of 196 +/- 27 (SEM) mg/dl. Thereafter glucose levels declined to normoglycaemic values (80-100 mg/dl), and with increasing age, mutants of both sexes became hypoglycaemic (60 mg/dl at 9 months). Mutants of both sexes were extremely hyperinsulinaemic at the earlier ages, with mean plasma insulin at months 5 reflecting 30-fold elevations above normal for males and 18-fold for females. These levels diminished with age, the decline being more marked in males. Plasma glucagon levels were 3-fold elevated in the younger mutants of both sexes (86 pg/ml versus 28 pg/ml in normal mice), mean levels increasing to almost 5-fold above mean control vaues in the older age group (198 pg/ml versus 41 pg/ml in normal mice). Histopathological findings were limited to pancreas. Increasing necrosis of the exocrine, but not endocrine, pancreas was noted in aging mutants. Aldehyde fushsin staining of the mutant pancreas revealed hyperplastic islets filled with heavily granulated B-cells. B-cell hyperplasia was accompanied by a 30-fold increase over controls in pancreatic insulin content in the 8 month old mutants, whereas pancreatic glucagon content was only doubled. Morphometric analysis showed less than a 2-fold increase in the mean number of A-cells per islet. Thus, an interesting feature of expression of the diabetes gene in the 129/J strain is the persisting hyperglucagonaemia in the face of moderating hyperinsulinaemia.


An open-label study of administration of EH0202, a health-food additive, to patients with chronic hepatitis C.
In this study, we examined the effect of EH0202, a mixture of four herbal extracts that are known to induce interferons, on hepatitis C virus (HCV)-RNA levels in patients with chronic hepatitis C. This was an open-label uncontrolled study. The study subjects ingested food containing EH0202 daily for 3 months, which was equivalent to 1 g of desiccated herbs daily. Clinical symptoms, hematology and biochemical examinations, urine, and HCV-RNA levels were examined before, during (1 month), and after the EH0202 treatment (3 months). Among the 35 patients who successfully completed the study, there were improvements in malaise (seen in 6 patients before and in 2 after EH0202 treatment), bloating sensation in the abdomen (seen in 2 before and in none after treatment), and nausea and vomiting (seen in 2 before and in 1 after treatment). There were no changes in hematology or biochemical examination parameters. There was a statistically significant decrease in HCV-RNA levels in patients with high viral titers after 3 months of EH0202 administration. No serious adverse events were observed with the EH0202 treatment. These findings suggest that EH0202 may be safe and useful in the treatment of patients with chronic hepatitis C. Further studies are, however, needed to obtain a definitive conclusion.


Protein structure prediction via combinatorial assembly of sub-structural units.
Following the hierarchical nature of protein folding, we propose a three-stage scheme for the prediction of a protein structure from its sequence. First, the sequence is cut to fragments that are each assigned a structure. Second, the assigned structures are combinatorially assembled to form the overall 3D organization. Third, highly ranked predicted arrangements are completed and refined. This work focuses on the second stage of this scheme: the combinatorial assembly. We present CombDock, a combinatorial docking algorithm. CombDock gets an ordered set of protein sub-structures and predicts the inter-contacts that define their overall organization. We reduce the combinatorial assembly to a graph-theory problem, and give a heuristic polynomial solution to this computationally hard problem. We applied CombDock to various examples of structural units of two types: protein domains and building blocks, which are relatively stable sub-structures of domains. Moreover, we tested CombDock using increasingly distorted input, where the native structural units were replaced by similarly folded units extracted from homologous proteins and, in the more difficult cases, from globally unrelated proteins. The algorithm is robust, showing low sensitivity to input distortion. This suggests that CombDock is a useful tool in protein structure prediction that may be applied to large target proteins.


The Life Esidimeni tragedy: Moral pathology and an ethical crisis.
The Life Esidimeni tragedy highlights several ethical transgressions. Health professionals' ethics are put to the test when their own interests are balanced against competing claims. Core values of compassion, competence and autonomy, together with respect for fundamental human rights, serve as the foundation of ethical practice in healthcare. These values are increasingly being challenged by governments and other third parties. The duties conferred on healthcare practitioners require them to act responsibly and be accountable for their actions. Codes in healthcare serve as a source of moral authority. The Gauteng health authorities exerted tremendous power and created a culture of fear and disempowerment among healthcare practitioners. When health professionals choose to support state interests instead of those of patients, problematic dual-loyalty conflicts arise.


Follow-up observations in patients with mitral valve prolapse.
The discrepancies reported in various studies with respect to long-term prognosis in mitral valve prolapse can be attributed to the criteria employed for diagnosis and to the differing patient populations studied. Furthermore, mitral valve prolapse is not a single, well-defined disease but reflects rather a broad spectrum of a disease process. Echocardiographically, patients can be identified with redundant, thickened leaflets with excessive mitral valve motion and prolapse as well as those with normal appearing leaflets but systolic prolapse representative of differing disease processes with differing prognosis. The incidence of sudden cardiac death is estimated at a low value of 1.9/10,000 patients per year. In the presence of a normal resting ECG, with no hemodynamically-meaningful mitral regurgitation and no evidence of redundant mitral leaflets the risk is even less. Cerebral embolic events occur with an estimated incidence of 1/6000 patients per year, similarly low; it can be assumed that patients with very myxomatous, redundant mitral leaflets have the highest risk. The incidence of infective endocarditis is also low, estimated at 1/5725 patients per year (0.175%). Risk factors for complications include: a systolic murmur, advanced age, male sex and leaflet redundancy. The most important complication is mitral regurgitation for which the incidence is highest in older men and in the presence of left ventricular, dilatation.


Superoxide-driven aconitase FE-S center cycling.
O2- produced by the autoxidation of respiratory chain electron carriers, and other cellular reductants, inactivates bacterial and mammalian iron-sulfur-containing (de)hydratases including the citric acid cycle enzyme aconitase. Release of the solvent-exposed iron atom and oxidation of the [4Fe-4S]2+ cluster accompanies loss of catalytic activity. Rapid reactivation is achieved by iron-sulfur cluster reduction and Fe2+ insertion. Inactivation-reactivation is a dynamic and cyclical process which modulates aconitase and (de)hydratase activities in Escherichia coli and mammalian cells. The balance of inactive and active aconitase provides a sensitive measure of the changes in steady-state O2- levels occurring in living cells and mitochondria under stress conditions. Aconitases are also inactivated by other oxidants including O2, H2O2, NO, and ONOO- which are associated with inflammation, hyperoxia and other pathophysiological conditions. Loss of aconitase activity during oxidant stress may impair energy production, and the liberation of reactive iron may further enhance oxidative damage. Iron-sulfur center cycling may also serve adaptive functions by modulating gene expression or by signaling metabolic quiescence.


Refractory anemia in the elderly.
Anatomical observations have indicated a decrease of marrow cellularity with age, but these changes are not associated with anemia in the healthy geriatric patient. Aged patients with refractory anemia should be studied by utilizing red cell volume (MCV) and red cell heterogeneity (RDW). A classification with these indices initially can separate the anemias for a more fruitful investigation. By old age the anemias of hereditary red cell membrane or hemoglobin disorders should be known to the patient. In the absence of tumor, elderly patients have an increasing frequency of refractory anemias that can be called preleukemia or myelodysplastic syndrome. Morphological observations have emphasized the importance of abnormal megakaryocytes and platelets in all phases of preleukemia, and these cytologic changes should be used to guide the physician in the early diagnosis of the syndrome complex. This group of refractory anemias have a limited survival, but nonspecific marrow stimulation can be effective and should be tried. With a more complete classification of the chromosomal abnormalities in the myelodysplastic syndrome, a more accurate prognosis can be anticipated. The anemias of marrow aplasia and ineffective iron utilization (anemia of chronic disease) are found frequently in the elderly, and the physician may offer more effective therapy by an early diagnosis.


Regulation of hepatic vitamin A storage in a rat model of controlled vitamin A status during aging.
It is currently unknown whether the capacity of the liver to esterify and store vitamin A (VA) changes as a function of long-term VA intake or age. The objective of this study was to investigate whether age and/or VA status are factors for the hepatic expression of cellular retinol-binding protein (CRBP), the esterification of retinol by lecithin:retinol acyltransferase (LRAT) and the accumulation of VA and lipids in liver. Two factors, VA intake and age, were studied in a 3x3 design. Diets denoted as VA-marginal, control and supplemented contained 0.35, 4 and 25 mg retinol equivalents/kg diet, respectively; male Lewis rats were fed these diets from weaning until the ages of 2-3 mo (young), 8-10 mo (middle-aged) and 18-20 mo (old) (n = 6/group. Liver CRBP mRNA differed (two-way ANOVA) with dietary VA (P<0.0001) and age (P<0.05). Hepatic LRAT activity increased with dietary VA (P<0.0001). Age was not a factor (P = 0.47) although there was an interaction of age and dietary VA (P<0.0001). Hepatic LRAT activity was correlated (r = 0.633, P<0.0001) with plasma retinol at physiologic concentrations. In VA-supplemented rats of all ages, the plasma molar ratio of total retinol:retinol-binding protein (RBP) exceeded 1, and liver VA and total lipid concentrations were elevated. However, tests of liver function had previously been shown to be within normal values. Thus, the capacity of the liver for retinol esterification by LRAT was not diminished by age or the accumulation of VA and other lipids. We conclude the following: 1) hepatic LRAT activity is regulated across a broad, physiologic range of dietary VA; 2) LRAT activity is regulated throughout life; and 3) the capacity for hepatic VA storage is high throughout life.


Real-time and non-invasive fluorescence tracking of in vivo degradation of the thermosensitive PEGlyated polyester hydrogel.
The real-time monitoring of materials degradation is crucial to determine the in vivo retention time and the design or screening of degradable biomaterials. However, in vivo performance cannot always be predicted through the traditional determination of in vitro erosion and current standard methods sacrifice samples or animals, preventing the sequential measurement of the same specimen. Herein, a non-invasive fluorescence imaging method was developed to sequentially follow in vivo loss of fluorescence signal to simultaneously characterize the hydrolytic and enzymatic degradation of PEGlyated polyester hydrogel. Rhodamine B was conjugated to thermosensitive amphiphilic triblock copolymer based on cyclic ether modified PCL and PEG (abbreviated as PECT) and no obvious influence on gelation time or gel strength was observed with the conjugation content under 0.121% (w/w). Both in vitro and in vivo degradation profiles followed linear fittings while in vivo and in vitro hydrogel degradation rates correlated in an exponential mathematical model, enabling the general prediction of in vivo erosion trends of new biomaterial formulations from in vitro data. This methodology possibly enabled rational design and rapid in vitro screening of degradable materials, and might be potentially extended to simultaneously determine the material erosion and speculate the drug release from a drug-incorporated scaffold, or the cell growth profile in tissue-engineering formulations.


Genetic Investigation of Consanguineous Pakistani Families Segregating Rare Spinocerebellar Disorders.
Spinocerebellar disorders are a vast group of rare neurogenetic conditions, generally characterized by overlapping clinical symptoms including progressive cerebellar ataxia, spastic paraparesis, cognitive deficiencies, skeletal/muscular and ocular abnormalities. The objective of the present study is to identify the underlying genetic causes of the rare spinocerebellar disorders in the Pakistani population. Herein, nine consanguineous families presenting different spinocerebellar phenotypes have been investigated using whole exome sequencing. Sanger sequencing was performed for segregation analysis in all the available individuals of each family. The molecular analysis of these families identified six novel pathogenic/likely pathogenic variants; ZFYVE26: c.1093del, SACS: c.1201C>T, BICD2: c.2156A>T, ALS2: c.2171-3T>G, ALS2: c.3145T>A, and B4GALNT1: c.334_335dup, and three already reported pathogenic variants; FA2H: c.159_176del, APTX: c.689T>G, and SETX: c.5308_5311del. The clinical features of all patients in each family are concurrent with the already reported cases. Hence, the current study expands the mutation spectrum of rare spinocerebellar disorders and implies the usefulness of next-generation sequencing in combination with clinical investigation for better diagnosis of these overlapping phenotypes.


Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors.
The clinical efficacy of chimeric antigen receptor (CAR)-redirected T cells remains marginal in solid tumors compared with leukemias. Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combined CAR-T cells with an oncolytic virus armed with the chemokine RANTES and the cytokine IL15, reasoning that the modified oncolytic virus will both have a direct lytic effect on infected malignant cells and facilitate migration and survival of CAR-T cells. Using neuroblastoma as a tumor model, we found that the adenovirus Ad5Δ24 exerted a potent, dose-dependent, cytotoxic effect on tumor cells, whereas CAR-T cells specific for the tumor antigen GD2 (GD2.CAR-T cells) were not damaged. When used in combination, Ad5Δ24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, whereas the intratumoral release of both RANTES and IL15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor-bearing mice. These preclinical data support the use of this innovative biologic platform of immunotherapy for solid tumors. Cancer Res; 74(18); 5195-205. ©2014 AACR.


[Organizing the supervision over the turnover of nanomaterials presenting a potential hazard to human health].
Nanoindustry encompasses very different branches of industry today. It should be noted that these are precisely the investigators who deal with researches and developments of nanomaterials will be to the largest measure exposed and hence the likelihood of the potential harm to their health is greatest. To elaborate the special regulations and programs, normative documents and guidelines designed to afford safety and health protection of the employees at work, which should consider the specific characteristics of nanotechnologies. Since 2007, work has proceeded on the safety evaluation of nanoparticles and nanomaterials. Nanotechnology as a key priority in the foreseeable future poses a number of problems facing hygiene science to develop hygienic safety criteria for the production, usage, utilization and storage of various nanomaterials and to elaborate procedures for determination of nanoparticles in different media. Russia will be able to rapidly progress in solving the safety problems in emerging nanoindustry and to minimize human health and environmental risks associated with the manufacture and use of nanoproducts.


Impaired reticuloendothelial function in patients treated with methyldopa.
In about 20 per cent of patients taking the antihypertensive agent methyldopa, IgG autoantibodies form against red cells, but most such patients do not have hemolysis. The reason for this is uncertain; it does not appear to be explained by known characteristics of the autoantibody. Since antibody-dependent reticuloendothelial function is an important determinant of cell clearance, we measured reticuloendothelial function in nine patients taking methyldopa. We did this by measuring the rate of clearance of radiolabeled autologous red cells sensitized with anti-D alloantibody. Five patients had a positive direct antiglobulin test, and four did not. Only one patient had laboratory evidence of hemolysis. The patients without hemolysis had significantly impaired reticuloendothelial clearance. In contrast, the patient with hemolysis did not have impaired reticuloendothelial function. This study suggests that in patients taking methyldopa who have a positive direct antiglobulin test the absence of hemolysis may be caused by an impairment in reticuloendothelial function. That the drug itself may be responsible for the impairment is suggested by the occurrence of abnormal reticuloendothelial function in patients taking the drug who have a negative direct antiglobulin test.


Fabrication of Lead-Free Bi0.5Na0.5TiO₃ Thin Films by Aqueous Chemical Solution Deposition.
Piezoelectric ceramics are widely used in actuator applications, and currently the vast majority of these devices are based on Pb ( Zr , Ti ) O 3 , which constitutes environmental and health hazards due to the toxicity of lead. One of the most promising lead-free material systems for actuators is based on Bi 0 . 5 Na 0 . 5 TiO 3 (BNT), and here we report on successful fabrication of BNT thin films by aqueous chemical solution deposition. The precursor solution used in the synthesis is based on bismuth citrate stabilized by ethanolamine, NaOH , and a Ti-citrate prepared from titanium tetraisopropoxide and citric acid. BNT thin films were deposited on SrTiO 3 and platinized silicon substrates by spin-coating, and the films were pyrolized and annealed by rapid thermal processing. The BNT perovskite phase formed after calcination at 500 °C in air. The deposited thin films were single phase according to X-ray diffraction, and the microstructures of the films shown by electron microscopy were homogeneous and dense. Decomposition of the gel was thoroughly investigated, and the conditions resulting in phase pure materials were identified. This new aqueous deposition route is low cost, robust, and suitable for development of BNT based thin film for actuator applications.


Sir2 mediates apoptosis through JNK-dependent pathways in Drosophila.
Increased expression of the histone deacetylase sir2 has been reported to extend the life span of diverse organisms including yeast, Caenorhabditis elegans, and Drosophila melanogaster. A small molecule activator of Sir2, resveratrol, has also been suggested to extend the fitness and survival of these simple model organisms as well as mice fed high calorie diets. However, other studies in yeast have shown that Sir2 itself may prevent life extension, and high expression levels of Sir2 can be toxic to yeast and mouse cells. This conflicting evidence highlights the importance of understanding the mechanisms by which Sir2 expression or activation affects survival of organisms. To investigate the downstream signaling pathways affected by Sir2 in Drosophila, we generated transgenic flies expressing sir2. Here, we show that overexpression of sir2 in Drosophila promotes caspase-dependent but p53-independent apoptosis that is mediated by the JNK and FOXO signaling pathways. Furthermore, we find that a loss-of-function sir2 mutant partially prevents apoptosis induced by UV irradiation in the eye. Together, these results suggest that Sir2 normally participates in the regulation of cell survival and death in Drosophila.


Visual processing in anorexia nervosa and body dysmorphic disorder: similarities, differences, and future research directions.
Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are psychiatric disorders that involve distortion of the experience of one's physical appearance. In AN, individuals believe that they are overweight, perceive their body as "fat," and are preoccupied with maintaining a low body weight. In BDD, individuals are preoccupied with misperceived defects in physical appearance, most often of the face. Distorted visual perception may contribute to these cardinal symptoms, and may be a common underlying phenotype. This review surveys the current literature on visual processing in AN and BDD, addressing lower- to higher-order stages of visual information processing and perception. We focus on peer-reviewed studies of AN and BDD that address ophthalmologic abnormalities, basic neural processing of visual input, integration of visual input with other systems, neuropsychological tests of visual processing, and representations of whole percepts (such as images of faces, bodies, and other objects). The literature suggests a pattern in both groups of over-attention to detail, reduced processing of global features, and a tendency to focus on symptom-specific details in their own images (body parts in AN, facial features in BDD), with cognitive strategy at least partially mediating the abnormalities. Visuospatial abnormalities were also evident when viewing images of others and for non-appearance related stimuli. Unfortunately no study has directly compared AN and BDD, and most studies were not designed to disentangle disease-related emotional responses from lower-order visual processing. We make recommendations for future studies to improve the understanding of visual processing abnormalities in AN and BDD.


In search of the microbe/mineral interface: quantitative analysis of bacteria on metal surfaces using vertical scanning interferometry.
To understand the development of biofilms on metal surfaces, analysis of initial bacterial attachment to surfaces is crucial. Here we present the results of a study, using Shewanella oneidensis MR-1 as a model organism, in which vertical scanning interferometry (VSI) was used to investigate the initial stages of cell attachment to glass, steel and aluminium surfaces. It was found that while VSI gave unambiguous results with opaque surfaces, when reflective surfaces were used, an artifact sometimes appeared, with the bacteria appearing as rod-shaped pits rather than as cells on the surface. When the bacteria were altered to increase opacity, this artifact disappeared, and upon further investigation, it was found that the observational artifact was the result of a conflict between light reflected from the bacteria and the light reflected from the bacteria-metal interface. These results suggest that not only can bacteria be measured on surfaces using VSI, but with some modifications to the analytical software, there may be a unique window for studying the bacterial/substrate interface that can be used for quantitative observations. Imaging and characterization of the bacteria-substrate interface in vivo (previously invisible) will provide new insights into the interactions that occur at this important juncture.


Impulse control disorders in non-treatment seeking hair pullers.
Background and aims Hair pulling is a common body focused repetitive behavior. The purpose of this paper is to examine the prevalence of impulse control disorders (as defined in DSM-IV-TR) in a non-treatment seeking sample of hair pullers. Methods 1,717 college students with (n = 44) and without (n = 1673) hair pulling completed a mental health survey. The college students were sent an online survey assessing hair pulling behavior and other impulse control disorders using the Minnesota Impulsive Disorders Interview. Results Students with hair pulling were significantly more likely to have a co-occurring impulse control disorder (20.5% vs. 8.9%, p = 0.009, OR = 2.71, CI = 1.28-5.75) and were significantly more likely to meet criteria for compulsive buying, compulsive sexual behavior and intermittent explosive disorder than students without hair pulling. Differences seemed to be moderated by the male gender among students with hair pulling. Discussion and conclusions Hair pulling is often comorbid with another impulse control disorder, which suggests that elements of impulsivity may be important in our understanding of hair pulling. Furthermore, gender may moderate impulse control comorbidity in hair pulling disorder.


Relative efficacy of parenteral haloperidol and thiothixene for the emergency treatment of acutely excited and agitated patients.
In this double-blind study, haloperidol (n = 15) and thiothixene (n = 15), administered parenterally in emergency rooms and outpatient facilities to 30 acutely excited, agitated psychotic patients in hourly doses of 4 mg. or 8 mg., as needed over a four-hour period (total dosage ranging from 4 to 32 mg.), achieved rapid tranquilization in 30 patients. Significant improvement was shown over a six-hour period on BPRS Total Score, the four factors--Thinking Disorder, Anergic state, Excitement and Disorientation, and Depression and also on hourly ratings of 17 symptoms of a Psychiatric Target Symptom Profile. No significant differences were found between the haloperidol-treated and thiothixene-treated groups. Few adverse reactions were noted, all of them mild, the most frequent being drowsiness in six patients.


Identification of a class of novel tubulin inhibitors.
We previously developed a series of anticancer agents based on cyclooxygenase-2 (COX-2) inhibitor nimesulide as a lead compound. However, the molecular targets of these agents still remain unclear. In this study, we synthesized a biotinylated probe based on a representative molecule of the compound library and performed protein pull-down assays to purify the anticancer targets of the compound. Via proteomic approaches, the major proteins bound to the probe were identified to be tubulin and heat shock protein 27 (Hsp27), and the compound inhibited tubulin polymerization by binding at the colchicine domain. However, the tubulin inhibitory effect of the compound activated the Hsp27 phosphorylation and possibly overrode the direct Hsp27 inhibitory effects, which made it difficult to solely validate the Hsp27 target. Taken together, the compound was a dual ligand of tubulin and Hsp27, inhibited tubulin polymerization, and had the potential to be a class of new chemotherapeutic agents.


An opposing function of paralogs in balancing developmental synapse maturation.
The disc-large (DLG)-membrane-associated guanylate kinase (MAGUK) family of proteins forms a central signaling hub of the glutamate receptor complex. Among this family, some proteins regulate developmental maturation of glutamatergic synapses, a process vulnerable to aberrations, which may lead to neurodevelopmental disorders. As is typical for paralogs, the DLG-MAGUK proteins postsynaptic density (PSD)-95 and PSD-93 share similar functional domains and were previously thought to regulate glutamatergic synapses similarly. Here, we show that they play opposing roles in glutamatergic synapse maturation. Specifically, PSD-95 promoted, whereas PSD-93 inhibited maturation of immature α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptor (AMPAR)-silent synapses in mouse cortex during development. Furthermore, through experience-dependent regulation of its protein levels, PSD-93 directly inhibited PSD-95's promoting effect on silent synapse maturation in the visual cortex. The concerted function of these two paralogs governed the critical period of juvenile ocular dominance plasticity (jODP), and fine-tuned visual perception during development. In contrast to the silent synapse-based mechanism of adjusting visual perception, visual acuity improved by different mechanisms. Thus, by controlling the pace of silent synapse maturation, the opposing but properly balanced actions of PSD-93 and PSD-95 are essential for fine-tuning cortical networks for receptive field integration during developmental critical periods, and imply aberrations in either direction of this process as potential causes for neurodevelopmental disorders.


Whole-genome characterization of Rosa chinensis AP2/ERF transcription factors and analysis of negative regulator RcDREB2B in Arabidopsis.
Rose (Rosa chinensis) is a traditional famous flower with valuable ornamental characteristics. However, drought stress restricts its growth and development, leading to an abnormal phenotype. One of the main transcription factor (TF) protein groups in the plant kingdom are the APETALA2/ethylene-responsive factor (AP2/ERF) proteins and are potentially involved in the growth and stress responses of various plants. Our investigation mainly focused on exploring the genome of rose and thereby we discovered 135 apparent AP2/ERF TFs. Phylogenic analyses revealed that RcAP2/ERF genes are categorized into DREB, Soloist, AP2, and ERF subfamilies, and are further classified these into 17 groups, with the same as Malus domestica and Arabidopsis thaliana. The analysis of the gene structure revealed that the introns ranged from 0 to 9 in number. Pattern examination demonstrated that the RcAP2/ERF predominantly consists of typical AP2 domains, of which the 2nd motif is the most ubiquitous. Distributions of cis-acting elements indicated that members of the AP2/ERF family are frequently involved in growth and development, phytohormone and stress response in rose species. Also, the distribution mapping of the rose chromosomes indicated that AP2/ERF class genes are dispersed among all seven chromosomes. Additionally, we isolated a novel DREB A2 subgroup gene and named it RcDREB2B. Subsequently, the RcDREB2B transcript accumulation was repressed under the mild and severe drought stress in the root samples of rose. RcDREB2B was targeted to the nucleus and exhibited transactivation in yeast cells. The overexpression of RcDREB2B was found to promote sensitivity to a higher salt concentration, ABA, and PEG at the germination and post-germination stages. Twelve putative osmotic and ABA-related genes were impaired in RcDREB2B-overexpressing plants. The results provide comprehensive information regarding the gene structure, phylogenic, and distribution of the rose AP2/ERF family and bring insight into the complex transcriptional gene regulation of RcAP2/ERF. Findings in this study would also contribute to further understanding of the RcDREB2B gene in rose.


Navigating Multidimensional Social-Ecological System Trade-Offs across Sanitation Alternatives in an Urban Informal Settlement.
Urban growth in low- and middle-income countries has intensified the need to expand sanitation infrastructure, especially in informal settlements. Sanitation approaches for these settings remain understudied, particularly regarding multidimensional social-ecological outcomes. Guided by a conceptual framework (developed in parallel with this study) re-envisioning sanitation as a human-derived resource system, here we characterize existing and alternative sanitation scenarios in an informal settlement in Kampala, Uganda. Combining two core research approaches (household survey analysis, process modeling), we elucidate factors associated with user satisfaction and evaluate each scenario's resource recovery potential, economic implications, and environmental impacts. We find that existing user satisfaction is associated with factors including cleaning frequency, sharing, and type of toilets, and we demonstrate that alternative sanitation systems may offer multidimensional improvements over existing latrines, drying beds, and lagoons. Transitioning to anaerobic treatment could recover energy while reducing overall net costs by 26-65% and greenhouse gas emissions by 38-59%. Alternatively, replacing pit latrines with container-based facilities greatly improves recovery potential in most cases (e.g., a 2- to 4-fold increase for nitrogen) and reduces emissions by 46-79%, although costs increase. Overall, this work illustrates how our conceptual framework can guide empirical research, offering insight into sanitation for informal settlements and more sustainable resource systems.


Wellbeing of School Communities in the Context of COVID-19 Pandemic: A Qualitative Study in Chilean Low-SES Schools.
The COVID-19 pandemic continues to impact schools and how education is conveyed to students. One of the aspects that has gained strength is supporting the wellbeing of educational communities. The purpose of this study was to describe and understand the construction of school wellbeing during the pandemic, based on the notion of collective and sustainable wellbeing. Through a qualitative design, we conducted a study in four Chilean low-SES schools in which a national school mental health program is implemented. A total of 41 in-depth interviews and one group interview were conducted with students, parents, teacher, teacher assistants, school principals, psychosocial professionals, and the school mental health officers during the second half of the 2020 school year. Thematic content analyses showed that, while facing the school closure challenges, schools strived to protect students' and teachers' wellbeing. However, participants highlighted necessary conditions for sustaining the school community's wellbeing and mental health in the context of the COVID-19 pandemic: assuring digital connectivity for all students; coordinated work with families and within the school; strengthening networks; curriculum adaptation and diversified pedagogical strategies; and emotional support toward teachers, families, and students. We discuss these findings and their implications for a sustainable and collective perspective of the wellbeing of school communities in low-SES schools, as well as for policy, practice, and research from the perspective of schools for social justice and health promotion.


Modeling and spatially distributing forest net primary production at the regional scale.
Forest, agricultural, rangeland, wetland, and urban landscapes have different rates of carbon sequestration and total carbon sequestration potential under alternative management options. Changes in the proportion and spatial distribution of land use could enhance or degrade that area's ability to sequester carbon in terrestrial ecosystems. As the ecosystems within a landscape change due to natural or anthropogenic processes, they may go from being a carbon sink to a carbon source or vice versa. Satellite image analysis has been tested for timely and accurate measurement of spatially explicit land use change and is well suited for use in inventory and monitoring of terrestrial carbon. The coupling of Landsat Thematic Mapper (TM) data with a physiologically based forest productivity model (PnET-II) and historic climatic data provides an opportunity to enhance field plot-based forest inventory and monitoring methodologies. We use periodic forest inventory data from the U.S. Department of Agriculture (USDA) Forest Service's Forest Inventory and Analysis (FIA) Program to obtain estimates of forest area and type and to generate estimates of carbon storage for evergreen, deciduous, and mixed-forest classes. The area information is used in an accuracy assessment of remotely sensed forest cover at the regional scale. The map display of modeled net primary production (NPP) shows a range of forest carbon storage potentials and their spatial relationship to other landscape features across the southern United States. This methodology addresses the potential for measuring and projecting forest carbon sequestration in the terrestrial biosphere of the southern United States.


A one-year randomized controlled psychosocial intervention study among family carers of dementia patients--effects on patients and carers.
To test the effect of a short-term psychosocial intervention programme for family carers of patients with dementia and identify characteristics of carers and patients that responded positively. The study was a multi-centre randomized controlled trial. Carers of 180 patients suffering from dementia recruited at 7 memory clinics at geriatric or psychiatric departments participated in the study. Carers of the intervention group were educated about dementia and in 6 group meetings taught how to use structured problem-solving. The control group received treatment as usual. The effect on patients was measured with the Neuropsychiatric Inventory and on carers with the Relatives' Stress Scale (RSS). The intention-to-treat efficacy analysis included 171 carer/patient dyads. The intervention did not have any effect on the primary outcome variables. The burden measured by the RSS increased in both groups; however, more carers of the control group converted from a low-burden group to a medium- or high-burden group after 4.5 months. In a subgroup analysis we found a statistically significant difference in the Neuropsychiatric Inventory score in favour of the intervention group among female patients. The predominately negative result of this study emphasizes the need of individually tailored interventions for carers and the use of narrow inclusion criteria when performing group-based interventions, such as the extent of burden as well as gender and kinship.


Evodiamine abolishes constitutive and inducible NF-kappaB activation by inhibiting IkappaBalpha kinase activation, thereby suppressing NF-kappaB-regulated antiapoptotic and metastatic gene expression, up-regulating apoptosis, and inhibiting invasion.
Evodiamine, an alkaloidal component extracted from the fruit of Evodiae fructus (Evodia rutaecarpa Benth., Rutaceae), exhibits antiproliferative, antimetastatic, and apoptotic activities through a poorly defined mechanism. Because several genes that regulate cellular proliferation, carcinogenesis, metastasis, and survival are regulated by nuclear factor-kappaB (NF-kappaB), we postulated that evodiamine mediates its activity by modulating NF-kappaB activation. In the present study, we investigated the effect of evodiamine on NF-kappaB and NF-kappaB-regulated gene expression activated by various carcinogens. We demonstrate that evodiamine was a highly potent inhibitor of NF-kappaB activation, and it abrogated both inducible and constitutive NF-kappaB activation. The inhibition corresponded with the sequential suppression of IkappaBalpha kinase activity, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acetylation. Evodiamine also inhibited tumor necrosis factor (TNF)-induced Akt activation and its association with IKK. Suppression of Akt activation was specific, because it had no effect on JNK or p38 MAPK activation. Evodiamine also inhibited the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK but not that activated by the p65 subunit of NF-kappaB. NF-kappaB-regulated gene products such as Cyclin D1, c-Myc, COX-2, MMP-9, ICAM-1, MDR1, Survivin, XIAP, IAP1, IAP2, FLIP, Bcl-2, Bcl-xL, and Bfl-1/A1 were all down-regulated by evodiamine. This down-regulation potentiated the apoptosis induced by cytokines and chemotherapeutic agents and suppressed TNF-induced invasive activity. Overall, our results indicated that evodiamine inhibits both constitutive and induced NF-kappaB activation and NF-kappaB-regulated gene expression and that this inhibition may provide a molecular basis for the ability of evodiamine to suppress proliferation, induce apoptosis, and inhibit metastasis.


Pharmacokinetics and pharmacodynamics of oral cephalexin in children with osteoarticular infections.
Osteoarticular infections lead to significant morbidity in children. Cephalexin has in vitro activity against methicillin-susceptible Staphylococcus aureus, a predominant pathogen in osteoarticular infection. However, cephalexin pharmacokinetics (PK) and pharmacodynamics (PD) are poorly described in children. This study described cephalexin PK in children treated for osteoarticular infection and assessed the proportion of children achieving surrogate PK/PD target for efficacy in methicillin-susceptible S. aureus infection. Children with osteoarticular infection, 1 to 18 years of age, were eligible for this study if they were receiving oral cephalexin per standard of care. PK plasma samples were collected at specified times after multiple doses. PK parameters were estimated using noncompartmental analysis. PK/PD target for efficacy was calculated using the child's PK parameters, minimum inhibitory concentration (MIC) of the isolate when available and previously described MIC of 2 and 4 mg/L. Twelve children were enrolled and PK profiles were obtained from 11 of them. Median age was 7 years, and median cephalexin dose was 40 mg/kg/dose every 8 hours. Median apparent oral clearance, apparent oral volume of distribution and elimination half-life (T1/2) were 0.29 L/h/kg, 0.44 L/kg and 1.1 h, respectively. Time above MIC (T>MIC) was greater than 40% of the dosing interval in 100%, 90% and 80% of the children when MICs were 0.25, 2 and 4 mg/L, respectively. Oral cephalexin achieved optimal plasma exposure and was well tolerated in children with osteoarticular infection. Correlation between osteoarticular infection clinical outcome and PK/PD parameters needs further evaluation.


Antibiofilm effect of trans-cinnamaldehyde on uropathogenic Escherichia coli.
Urinary tract infections are the most common hospital acquired infections in humans, caused primarily by uropathogenic Escherichia coli. Indwelling urinary catheters for bladder drainage in humans become encrusted with uropathogenic E. coli biofilms that are resistant to common antibiotics, resulting in chronic infections. We studied the efficacy of the cinnamon ingredient trans-cinnamaldehyde (Sigma) for preventing uropathogenic E. coli biofilm. We also determined the efficacy of trans-cinnamaldehyde as an ingredient in catheter lock solution to inactivate preformed uropathogenic E. coli biofilm. Polystyrene plates and urinary catheters inoculated with uropathogenic E. coli (5 to 6.0 log cfu) were treated with trans-cinnamaldehyde (0%, 0.1%, 0.25% or 0.5%) at 37C. Catheters with uropathogenic E. coli biofilm were also treated with lock solution containing trans-cinnamaldehyde (0%, 1%, 1.25% or 1.5%). Uropathogenic E. coli biofilm on control and trans-cinnamaldehyde treated plates and catheters was determined on incubation days 0, 1, 3 and 5. Trans-cinnamaldehyde potential cytotoxity, if any, was determined in HTB-4 bladder epithelial cells (ATCC). At all concentrations trans-cinnamaldehyde effectively prevented uropathogenic E. coli biofilm on plates and catheters. As a constituent in catheter lock solution, it inactivated uropathogenic E. coli biofilm on catheters. Trans-cinnamaldehyde produced no cytotoxic effects on human bladder epithelial cells at the tested concentrations. Results suggest that trans-cinnamaldehyde may be applied as a catheter surface coating or as an ingredient in catheter lock solution to prevent urinary tract infection in humans.


[Interactions between microbes and enterocytes in experimental intestinal infections].
All enteropathogens first attach to the glycocalyx on the enterocyte surface. Then noninvasive cholera vibrios and enterotoxicogenic E. coli multiply on the enterocyte microvilli producing enterotoxins which cause pronounced enterocyte hypersecretion. Invasive enteropathogens differ in the model of penetration into enterocytes, multiplication site, the effect on the fate of invaded enterocytes, the ability of the infectious process for generalization. Recent studies have confirmed the decisive role of Shigella intraepithelial multiplication in the development of ulcerative dysenteric mucosal inflammation, Salmonella penetration through the enterocytes, multiplication in macrophages and development of not only enterocolitis but generalized infection as well. In case of enteropathogenic E. coli causing infantile enteritis, multiplication of the attached germs with the resulting damage to the enterocyte surface plays the main role whereas bacterial invasion through the enterocytes is limited and of secondary importance. All the invasive enterobacteria produce peculiar cytotoxic enterotoxins which stimulate but also damage the enterocytes.


Social inequalities in patient experiences with general practice and in access to specialists: the population-based HUNT Study.
In countries with gatekeeping and equitable access to general practitioners (GPs), social inequalities in GP-patient interaction could be an important mechanism by which inequalities in access to medical specialists arise. The aim of this study was to investigate whether socioeconomic inequalities in experiences with general practice are associated with socioeconomic inequalities in access to specialist services. The study included 6,067 participants in the third survey of the Nord-Trøndelag Health Study (HUNT3, 2006-08) who were asked to evaluate their experiences with primary care and their regular general practitioner in Norway. Self-reported data on health status and number of visits to GP and specialist services in the last 12 months were included in the study. Socioeconomic status was measured by education and household income and rescaled to relative index of inequality (RII). Relative risks were calculated using Poisson regression. We found that a majority of patients reported positive experiences with general practice. Low socioeconomic status (SES) and male gender were associated with negative experiences. Patient experiences both directly and indirectly related to referrals were associated with the probability and quantity of specialist utilization: perception of low subjective influence on decisions about choice of medical care was associated with lower probability and quantity of specialist utilization, whereas desire to change the regular GP or to use GPs other than the regular GP and critical evaluations of the GP were associated with higher specialist consultation frequency. However, the level of education-related inequity in access to specialists was not sensitive to adjustment by survey responses. Patient experiences with general practice were associated with the patients' level of utilization of specialist services. There are socioeconomic inequalities in patient experiences with general practice, however the aspects measured in this study do not explain the observed socioeconomic inequity in access to specialists.


Compositional alterations in soil bacterial communities exposed to TiO2 nanoparticles are not reflected in functional impacts.
Titanium dioxide nanoparticles (TiO2NP) are increasingly released in soil ecosystems, while there is limited understanding of the impacts of TiO2NP on soil bacterial communities. Here we investigated the effects of TiO2NP on the taxonomic composition and functional profile of a soil bacterial community over a 60-day exposure period. In short-term exposure (1-day), contradictory effects on the taxonomic composition of soil bacterial communities were found after exposure to a low realistic environmental concentration of TiO2NP at 1 mg/kg as compared to the effects induced by medium and high concentrations of TiO2NP at 500 and 2000 mg/kg. After long-term exposure (60-day), the negative effects of TiO2NP at the low concentration disappeared, and the inhibition by TiO2NP of the abundance of core taxa was enhanced along with increasing exposure concentrations. However, although significant alterations were observed in the taxonomic composition over time and exposure concentrations, no significant change was observed in the community functional profile as well as enzyme activity after 60-day exposure, indicating that functional redundancy likely contributed to the bacterial community tolerance after the exposure to TiO2NP. Our study highlighted the importance of assessing bacterial community compositional and functional responses in assessing the environmental risk of nanoparticles on soil ecosystems.


Renal Function Improvement Following ANG-3777 Treatment in Patients at High Risk for Delayed Graft Function After Kidney Transplantation.
Patients (20%-50%) undergoing renal transplantation experience acute kidney injury resulting in delayed graft function. ANG-3777 is an hepatocyte growth factor mimetic that binds to the c-MET receptor. In animal models, ANG-3777 decreases apoptosis, increases proliferation, and promotes organ repair and function. This was a randomized, double-blind, placebo-controlled, phase 2 trial of patients undergoing renal transplantation with <50 cc/h urine output for 8 consecutive hours over the first 24 hours posttransplantation, or creatinine reduction ratio <30% from pretransplantation to 24 hours posttransplantation. Subjects were randomized as 2:1 to 3, once-daily IV infusions of ANG-3777, 2 mg/kg (n = 19), or placebo (n = 9). Primary endpoint: time in days to achieve ≥1200 cc urine for 24 hours. Patients treated with ANG-3777 were more likely to achieve the primary endpoint of 1200 cc urine for 24 hours by 28 days posttransplantation (83.3% versus 50% placebo; log-rank test: χ2 = 2.799, P = 0.09). Compared with placebo, patients in the ANG-3777 arm had larger increases in urine output; lower serum creatinine; greater reduction in C-reactive protein and neutrophil gelatinase-associated lipocalin; fewer dialysis sessions and shorter duration of dialysis; fewer hospital days; significantly less graft failure; and higher estimated glomerular filtration rate. Adverse events occurred in a similar percentage of subjects in both arms. Events per subject were twice as high in the placebo arm. There was an efficacy signal for improved renal function in subjects treated with ANG-3777 relative to placebo, with a good safety profile.


Propagation and absorption of light in planar dielectric waveguides with two-dimensional semiconductors.
Strong optical responses of atomically thin two-dimensional (2D) semiconductors make them attractive candidates for integration into various photonic and optoelectronic structures. We discuss some fundamental effects of such integration into planar dielectric waveguides by demonstrating that a substantial modification of the spectrum of waveguide modes can occur due to high in-plane polarizability of 2D layers. Our calculations illustrate both the conceptual possibilities associated with sharp excitonic resonances as well as the results obtained with the experimentally assessed polarizability of monolayer MoS2 over a broad spectral range. We point out that waveguide structures could also enable the tunable absorption by 2D semiconductors of the light that propagates along them, a modality quite different from the traditional light harvesting geometry.


Contraception at the time of abortion: high-risk time or high-risk women?
Despite the widespread use of highly effective contraception in France, the incidence of abortion is high. A retrospective population-based cohort study was designed to analyse women's contraceptive history. We compared the contraceptive use of 163 women, whose last pregnancy ended in abortion, 6 months before, at the time of, 1 month and 6 months after the event with that of 1787 women who had never had an abortion. A total of 46% of women who experienced an abortion used a highly effective form of contraception 6 months before the event (versus 76% among women who had never had an abortion, P < 0.001). This proportion dropped to 33% at the time of the abortion and increased to 71%, 1 month after. In addition, 50% of women who had an abortion had changed their contraceptive method in the 6 months before the event (compared with 16% in the 6 months before the interview in women who had not had an abortion, P < 0.001). Women with socially deprived backgrounds were less likely to use a highly effective contraception after an abortion. Abortion is a good opportunity for intervention, but especially so for socially disadvantaged women. It is essential to draw the attention of prescribers and women to the higher risk of contraceptive failure at the start of use of a method.


Reactive astrocytes are key players in nigrostriatal dopaminergic neurorepair in the MPTP mouse model of Parkinson's disease: focus on endogenous neurorestoration.
Parkinsons'disease (PD), a common neurodegenerative disorder, is characterized by progressive loss of dopaminergic (DAergic) neurons in the subtantia nigra pars compacta (SNpc) and gliosis. The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are not completely clarified, but interactions between genes and environmental factors are recognized to play a critical role in modulating the vulnerability to PD. Current evidence points to reactive glia as a pivotal factor in PD, but whether astroglia activation may protect or exacerbate DAergic neuron loss is presently the subject of much debate. Astrocytes and microglia are the key players in neuroinflammatory responses, by secreting an array of pro- and anti-inflammatory cytokines, anti-oxidant and neurotrophic factors. Here, the contribution of astrocytes and their ability to influence DAergic neurodegeneration, neuroprotection and neurorepair will be discussed. In particular, the dynamic interplay between astrocyte-derived factors and neurogenic signals in MPTP-induced plasticity of nigrostriatal DAergic neurons will be summarized together with recent findings showing that reactive astrocytes may contribute to promote DAergic neurogenesis from midbrain adult neural stem/precursor cells (NPCs). Within a host of astrocyte- derived factors, we unveiled Wingless-type MMTV integration site (Wnt)/β-catenin signalling was unveiled, as a strong candidate in MPTP-induced DAergic neuroplasticty/neurorepair. Understanding the intrinsic plasticity of nigrostriatal DAergic neurons and decifering the signals facilitating the crosstalk between astrocytes and midbrain neuroprogenitors may have implications for the role of stem cells technology in PD and for identifying potential therapeutic targets to promote endogenous neurorepair.


[Adsorption of methylene blue from water by the biochars generated from crop residues].
Biochars were prepared from straws of rice, peanut and soybean and rice hull using a low temperature pyrolysis method and adsorption of methylene blue by these biochars were investigated with batch and leaching experiments. Results indicated that biochars have high adsorption capacity for methylene blue and followed the order: rice straw char > soybean straw char > peanut straw char > rice hull char. This order is generally consistent with the amount of negative charge and specific surface area of these biochars. While methylene blue was mainly adsorbed specifically by the biochars, because the adsorption of methylene blue increased with the increase of ionic strength and the adsorption led to the shift of zeta potential of biochar particles to positive value direction. Langmuir equation fitted the adsorption isotherms well and can be used to describe the adsorption behaviors of methylene blue by the biochars. The maximum adsorption capacity of methylene blue predicted by langmuir equation was 196.1, 169.5, 129.9 and 89.3 mmol x kg(-1) for rice straw char, soybean straw char, peanut straw char and rice hull char, respectively. Leaching experiments show that rice hull char of 156 g can remove methylene blue from 30 L water containing 0.3 mmol x L(-1) of methylene blue completely and the cumulative amount of methylene blue absorbed by the biochar reaches 57.7 mmol x kg(-1). The biochars can be used as efficient adsorbents to remove methylene blue from waste water of dye.


Liposomal Formulations in Clinical Use: An Updated Review.
Liposomes are the first nano drug delivery systems that have been successfully translated into real-time clinical applications. These closed bilayer phospholipid vesicles have witnessed many technical advances in recent years since their first development in 1965. Delivery of therapeutics by liposomes alters their biodistribution profile, which further enhances the therapeutic index of various drugs. Extensive research is being carried out using these nano drug delivery systems in diverse areas including the delivery of anti-cancer, anti-fungal, anti-inflammatory drugs and therapeutic genes. The significant contribution of liposomes as drug delivery systems in the healthcare sector is known by many clinical products, e.g., Doxil®, Ambisome®, DepoDur™, etc. This review provides a detailed update on liposomal technologies e.g., DepoFoam™ Technology, Stealth technology, etc., the formulation aspects of clinically used products and ongoing clinical trials on liposomes.


Inhibition of human leukocyte elastase by mineral dust particles.
After isolation, purification, and radiolabeling of elastin from baboon aorta and lung, the rates of hydrolysis of both 3H-labeled elastins by porcine pancreatic elastase (PPE or by human leukocyte elastase (HLE) were compared. PPE (30 nM) degraded aorta and lung elastins at rates of 40 and 75 micrograms/h, respectively, leading to their complete solubilization. In contrast, the low rate of hydrolysis of lung elastin (10 micrograms/h) by HLE was paradoxically accompanied with a fivefold decrease in the Michaelis constant value and became negligible after 1 h of incubation. Moreover, HLE adsorption isotherms showed that 0.87 nmol HLE was adsorbed on 1 mg of aorta elastin vs. 1.30 nmol/mg lung elastin. Also, increasing ionic strength was found to enhance the elastolytic potential of HLE toward lung elastin. Investigations were carried out to explain why baboon lung elastin exhibited low susceptibility to hydrolysis by HLE. Solubilization of lung elastin with PPE produced a residue that exhibited inhibitory capacity toward HLE when either 3H-labeled aorta elastin or succinyl trialanine nitroanilide was used as a substrate. When analyzed by transmission electron microscopy, this residue was found to consist of several mineral dust particles, mainly kaolinite (53%) of environmental origin. The HLE-inhibitory capacities of various mineral or coal mine dust particles were then analyzed. Mineral aluminium-silicate dusts were found to be potent HLE inhibitors: 5 micrograms of either kaolinite or montmorillonite totally abolished the activity of 0.45 micrograms of HLE. All these results allowed us to propose that HLE inhibition by aluminium-silicate dusts may be of importance in the pathogenesis of industrial pneumoconiosis and in opportunistic lung infections.


Extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 mitogen-activated protein kinase signaling and activation of activator protein 1 and nuclear factor kappaB transcription factors play central roles in interleukin-8 expression stimulated by monosodium urate monohydrate and calcium pyrophosphate crystals in monocytic cells.
Monosodium urate monohydrate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals cause acute gout and pseudogout, respectively. Because acute gout and pseudogout appear to be dependent on interleukin-8 (IL-8)-induced neutrophil ingress, this study was undertaken to define and compare how MSU and CPPD crystals stimulate IL-8 messenger RNA (mRNA) expression in mononuclear phagocytes. MSU and CPPD crystal-induced mitogen-activated protein kinase (MAPK) signal transduction and IL-8 transcriptional activation were studied in human monocytic cells, using the THP-1 cell line. MSU and CPPD crystals (0.5 mg/ml) induced activation of c-Jun N-terminal kinase, extracellular signal-regulated kinase 1 (ERK-1)/ERK-2, and p38 MAPK pathways in THP-1 cells. Activation of the ERK-1/ERK-2 pathway was essential for MSU and CPPD crystal-induced IL-8 mRNA expression, whereas the p38 pathway played a greater role in IL-8 mRNA expression in response to CPPD crystals in comparison with MSU crystals. Both crystals induced the binding of nuclear factor kappaB (NF-kappaB), including the NF-kappaB complex c-Rel/RelA, and activator protein 1 (AP-1, including N-terminal phosphorylated c-Jun) to the IL-8 promoter. Both crystals induced transcriptional activation of the IL-8 promoter, which was dependent on activation of c-Rel/RelA and AP-1. Activation of the NF-IL-6 transcription factor played a lesser role. Finally, crystal-induced IL-8 promoter activation was mediated by activation of the ERK-1/ERK-2 pathway, as demonstrated by transfection of dominant-negative raf-1. These results indicate that ERK-1/ ERK-2 signaling and transcriptional activation through AP-1 and NF-kappaB are essential for the induction of IL-8 expression in mononuclear phagocytes in response to CPPD and MSU crystals.


Positive inotropic and lusitropic effects of HNO/NO- in failing hearts: independence from beta-adrenergic signaling.
Nitroxyl anion (HNONO(-)), the one-electron reduced form of nitric oxide (NO), induces positive cardiac inotropy and selective venodilation in the normal in vivo circulation. Here we tested whether HNO/NO(-) augments systolic and diastolic function of failing hearts, and whether contrary to NO/nitrates such modulation enhances rather than blunts beta-adrenergic stimulation and is accompanied by increased plasma calcitonin gene-related peptide (CGRP). HNO/NO(-) generated by Angelis' salt (AS) was infused (10 microg/kg per min, i.v.) to conscious dogs with cardiac failure induced by chronic tachycardia pacing. AS nearly doubled contractility, enhanced relaxation, and lowered cardiac preload and afterload (all P < 0.001) without altering plasma cGMP. This contrasted to modest systolic depression induced by an NO donor diethylamine(DEA)NO or nitroglycerin (NTG). Cardiotropic changes from AS were similar in failing hearts as in controls despite depressed beta-adrenergic and calcium signaling in the former. Inotropic effects of AS were additive to dobutamine, whereas DEA/NO blunted beta-stimulation and NTG was neutral. Administration of propranolol to nonfailing hearts fully blocked isoproterenol stimulation but had minimal effect on AS inotropy and enhanced lusitropy. Arterial plasma CGRP rose 3-fold with AS but was unaltered by DEA/NO or NTG, supporting a proposed role of this peptide to HNO/NO(-) cardiotropic action. Thus, HNO/NO(-) has positive inotropic and lusitropic action, which unlike NO/nitrates is independent and additive to beta-adrenergic stimulation and stimulates CGRP release. This suggests potential of HNO/NO(-) donors for the treatment of heart failure.


Qualitative and Quantitative Analysis of Primary Neocortical Areas in Selected Mammals.
The present study focuses on the relationship between neocortical structures and functional aspects in three selected mammalian species. Our aim was to compare cortical layering and neuron density in the projection areas (somatomotor, M1; somatosensory, S1; auditory, A1; and visual, V1; each in a wider sense). Morphological and design-based stereological analysis was performed in the wild boar (Sus scrofa scrofa) as a representative terrestrial hoofed animal (artiodactyl) and the common dolphin (Delphinus delphis) as a highly derived related aquatic mammal (cetartiodactyl). For comparison, we included the human (Homo sapiens) as a well-documented anthropoid primate. In the cortex of many mammals, layer IV (inner granular layer) is the main target of specific thalamocortical inputs while layers III and V are the main origins of neocortical projections. Because the fourth layer is indistinct or mostly lacking in the primary neocortex of the wild boar and dolphins, respectively, we analyzed the adjacent layers III and V in these animals. In the human, all the three layers were investigated separately. The stereological data show comparatively low neuron densities in all areas of the wild boar and high cell counts in the human (as expected), particularly in the primary visual cortex. The common dolphin, in general, holds an intermediate position in terms of neuron density but exhibits higher values than the human in a few layers. With respect to the situation in the wild boar, stereological neuron counts in the dolphin are consistently higher, with a maximum in layer III of the visual cortex. The extended auditory neocortical field in dolphins and the hypertrophic auditory pathway indicate secondary neurobiological adaptations to their aquatic habitat during evolution. The wild boar, however, an omnivorous quadruped terrestrial mammal, shows striking specializations as to the sensorimotor neurobiology of the snout region.


Clustering of contacts relevant to the spread of infectious disease.
Infectious disease spread depends on contact rates between infectious and susceptible individuals. Transmission models are commonly informed using empirically collected contact data, but the relevance of different contact types to transmission is still not well understood. Some studies select contacts based on a single characteristic such as proximity (physical/non-physical), location, duration or frequency. This study aimed to explore whether clusters of contacts similar to each other across multiple characteristics could better explain disease transmission. Individual contact data from the POLYMOD survey in Poland, Great Britain, Belgium, Finland and Italy were grouped into clusters by the k medoids clustering algorithm with a Manhattan distance metric to stratify contacts using all four characteristics. Contact clusters were then used to fit a transmission model to sero-epidemiological data for varicella-zoster virus (VZV) in each country. Across the five countries, 9-15 clusters were found to optimise both quality of clustering (measured using average silhouette width) and quality of fit (measured using several information criteria). Of these, 2-3 clusters were most relevant to VZV transmission, characterised by (i) 1-2 clusters of age-assortative contacts in schools, (ii) a cluster of less age-assortative contacts in non-school settings. Quality of fit was similar to using contacts stratified by a single characteristic, providing validation that single stratifications are appropriate. However, using clustering to stratify contacts using multiple characteristics provided insight into the structures underlying infection transmission, particularly the role of age-assortative contacts, involving school age children, for VZV transmission between households.


Imbalance of RANKL/RANK/OPG system in interface tissue in loosening of total hip replacement.
In the differentiation of osteoclasts the differentiation factor (RANKL) interacts with the receptor activator of NF-kappaB (RANK) in a direct cell-to-cell contact between osteoblast and (pre)osteoclast. This is inhibited by soluble osteoprotegerin (OPG). The mRNA levels of both RANKL (p < 0.01) and RANK (p < 0.05) were high in peri-implant tissue and RANKL+ and RANK+ cells were found in such tissue. Double labelling also disclosed soluble RANKL bound to RANK+ cells. We were unable to stimulate fibroblasts to express RANKL in vitro, but monocyte activation with LPS gave a fivefold increase in RANK mRNA levels. In contrast to RANKL and RANK expression in peri-implant tissue, expression of OPG was restricted to vascular endothelium. Endothelial cell OPG mRNA levels were regulated by TNF-alpha and VEGF, but not by hypoxia. It is concluded that activated cells in the interface tissue overproduce both RANKL and RANK and they can interact without interference by OPG.


Liposomal phytohemagglutinin: In vivo T-cell activator as a novel pan-cancer immunotherapy.
Immunotherapy is an attractive approach for treating cancer. T-cell engagers (TCEs) are a type of immunotherapy that are highly efficacious; however, they are challenged by weak T-cell activation and short persistence. Therefore, alternative solutions to induce greater activation and persistence of T cells during TCE immunotherapy is needed. Methods to activate T cells include the use of lectins, such as phytohemagglutinin (PHA). PHA has not been used to activate T cells in vivo, for immunotherapy, due to its biological instability and toxicity. An approach to overcome the limitations of PHA while also preserving its function is needed. In this study, we report a liposomal PHA which increased PHA stability, reduced toxicity and performed as an immunotherapeutic that is able to activate T cells for the use in future cancer immunotherapies to circumvent current obstacles in immunosuppression and T-cell exhaustion.


Proposal to extend the PROMIS® item bank v2.0 'Ability to Participate in Social Roles and Activities': item generation and content validity.
Previous research indicated that the Patient-Reported Outcomes Measurement Information System (PROMIS®) item bank v2.0 'Ability to Participate in Social Roles and Activities' may miss subdomains of social participation. The purpose of this study was to generate items for these missing subdomains and to evaluate their content validity. A three-step approach was followed: (1) Item generation for 16 International Classification of Functioning Disability and Health subdomains currently not covered by the item bank; (2) Evaluation of content validity of generated items through expert review (n = 20) and think-aloud interviews with a purposeful sample of people with and without (chronic) health conditions (n = 10), to assess item comprehensibility, relevance, and comprehensiveness; and 3) Item revision based on the results of step 2, in a consensus procedure. First, 48 items were generated. Second, overall, content experts indicated that the generated items were relevant. Furthermore, based on experts' responses, items were simplified and 'participation in social media' was identified as an important additional subdomain of social participation. Additionally, 'participating in various social roles simultaneously' was identified as a missing item. Based on the responses of the interviewed adults items were simplified. Third, in total 17 items, covering 17 subdomains, were proposed to be added to the original item bank. The relevance, comprehensibility and comprehensiveness of the 17 proposed items were supported. Whether the proposed extension of the item bank leads to better psychometric properties of the item bank should be tested in a large-scale field study.


Catalytic chain-breaking pyridinol antioxidants.
When assayed for their capacity to inhibit azo-initiated peroxidation of linoleic acid in a water/chlorobenzene two-phase system, tellurium-containing 3-pyridinols were readily regenerable by N-acetylcysteine contained in the aqueous phase. The best inhibitors quenched peroxyl radicals more efficiently than alpha-tocopherol, and the duration of inhibition was limited only by the availability of the thiol reducing agent. The compounds were also found to catalyze reduction of hydrogen peroxide in the presence of thiol reducing agent.


Soybean Calmodulin-Binding Transcription Activators, GmCAMTA2 and GmCAMTA8, Coordinate the Circadian Regulation of Developmental Processes and Drought Stress Responses.
The calmodulin-binding transcription activators (CAMTAs) mediate transcriptional regulation of development, growth, and responses to various environmental stresses in plants. To understand the biological roles of soybean CAMTA (GmCAMTA) family members in response to abiotic stresses, we characterized expression patterns of 15 GmCAMTA genes in response to various abiotic stresses. The GmCAMTA genes exhibited distinct circadian regulation expression patterns and were differently expressed in response to salt, drought, and cold stresses. Interestingly, the expression levels of GmCAMTA2, GmCAMTA8, and GmCAMTA12 were higher in stem tissue than in other soybean tissues. To determine the roles of GmCAMTAs in the regulation of developmental processes and stress responses, we isolated GmCAMTA2 and GmCAMTA8 cDNAs from soybean and generated Arabidopsis overexpressing transgenic plants. The GmCAMTA2-OX and GmCAMTA8-OX plants showed hypersensitivity to drought stress. The water in the leaves of GmCAMTA2-OX and GmCAMTA8-OX plants was lost faster than that in wild-type (WT) plants under drought-stress conditions. In addition, stress-responsive genes were down-regulated in the GmCAMTA2-OX and GmCAMTA8-OX plants under drought stress conditions compared to WT plants. Our results suggest that GmCAMTA2 and GmCAMTA8 genes are regulated by circadian rhythms and function as negative regulators in development and drought stress responses.


A new noninvasive technique for imaging atherosclerotic plaque in the aortic arch of stroke patients by transcutaneous real-time B-mode ultrasonography: an initial report.
Aortic arch atherosclerotic plaque is a probable source of atheroembolic stroke. Transesophageal echocardiography (TEE) has been used to image the aorta of patients with stroke to identify atherosclerotic plaque. TEE is moderately invasive and does not always visualize plaques present in the distal ascending aorta and proximal aortic arch. In the current study, transcutaneous B-mode ultrasonography was performed to image the aortic arch through a lateral supraclavicular window, and the results were compared with those of TEE in 20 patients. The aorta was subdivided into the proximal ascending (PAsc), distal ascending (DAsc), proximal aortic arch (PAA), and distal aortic arch (DAA) to be certain the plaques identified by each technique were the same. Plaques were characterized as simple (<4 mm thick) or complex (>4 mm thick). In the PAsc, 8 simple plaques were identified with TEE but not with B-mode. In the DAsc, 1 complex plaque was identified with both techniques, and B-mode identified 1 additional complex and 1 simple plaque. In the PAA, 6 simple and 5 complex plaques were identified by both techniques, and TEE identified 1 additional complex plaque. In the DAA, TEE identified 2 simple and 2 complex plaques; B-mode identified 3 complex plaques. B-mode imaging compared favorably with TEE in identification of plaques in the aortic arch and distal ascending aorta, although it could not identify simple plaques in the proximal ascending. B-mode could visualize plaques not seen by TEE in the distal ascending aorta. B-mode ultrasonography is complementary to TEE in performance of a comprehensive assessment of plaque in the aortic arch and provides a noninvasive method for sequential studies of plaques that can be visualized.


Size-Specific Infrared Spectra of Benzene-(H2O)n Clusters (n = 1 through 7): Evidence for Noncyclic (H2O)n Structures.
Resonant ion-dip infrared spectroscopy has been used to record size-specific infrared spectra of C(6)H(6)-(H(2)O)n clusters with n = 1 through 7 in the O-H stretch region. The O-H stretch spectra show a dramatic dependence on cluster size. For the n = 3 to 5 clusters, the transitions can be divided into three types-attributable to free, pi hydrogen-bonded, and single donor water-water O-H stretches-consistent with a C(6)H(6)-(H(2)O)n structure in which benzene is on the surface of a cyclic (H(2)O)n cluster. In n = 6 and 7 clusters, the spectra show distinct new transitions in the 3500 to 3600 wave number region. After comparison of these results with the predictions of ab initio calculations on (H(2)O)n clusters, these new transitions have been assigned to double donor O-H stretches associated with the formation of a more compact, noncyclic structure beginning with (H(2)O)(6). This is the same size cluster for which ab initio calculations predict that a changeover to noncyclic (H(2)O)n structures will occur.